The broad long-term objective of this project is to develop computational models to gain a quantitative understanding of angiogenesis in skeletal muscle in response to exercise or to administration of exogenous growth factors. Experimental data are available that include measurements of expression ofvascular endothelial growth factor (VEGF) and its receptors, and of metalloproteinases (MMP) during and following muscle stimulation. Several key processes of angiogenesis in rat and human skeletal muscle will be studied using computational modeling. Models will be based on principles of biochemical kinetics and mass transport. Specific Aim 1will quantify the dynamics of VEGF interactions with its receptors during and following stimulation in rat muscles. A novel molecular-level model will be formulated that will include major VEGF isoforms, their endothelial cell high-affinity receptors VEGFR1 and VEGFR2, neuropilins, and heparan sulfate proteoglycansat the cell surface and in the basement membrane and extracellular matrix. Specific Aim 2 will analyze important aspects of capillary sprout formation by describing the proteolytic degradation of the basement membrane on the pre-existing microvessels and of the extracellular matrix. Models will include collagen, MMPs, membrane-type metalloproteinases, tissue inhibitor of metalloproteinases and other macro-molecules. In Specific Aim 3 the models will be applied to human muscle under physiological exercise and under conditions of exogenous administration of VEGF and its homolog, placenta! growth factor (PIGF). In therapeutic angiogenesis for peripheral vascular disease, intravascular or intramuscular administration of VEGF have been studied extensively in recent years, but the quantitative understanding of these procedures is incomplete. This research will provide a quantitative description of important processes leading to signal transduction events and neovascularization. It will have an impact on understanding both basic mechanisms of angiogenesis and therapeutic applications in peripheral vascular disease.